Ophthalmic fluid

ABSTRACT

An ophthalmic fluid containing at least one triglyceride, diglyceride, or monoglyceride which is chemically similar or compatible with compounds found naturally in the lipid layer of the tear film of an ocular substrate. Preferably the glycerides are derived from a fatty acid containing at least one unsaturated bond in a cis-configuration in the fatty acid residue. The ophthalmic fluid is arranged in use to provide a protective film across a tear film of an ocular substrate. Furthermore, the ophthalmic fluid is also arranged in use to provide a protective film intermediate a lipid layer of the tear film of the ocular substrate and a contact lens.

FIELD OF THE INVENTION

The present invention relates to an ophthalmic fluid for improving wearcomfort of contact lenses.

BACKGROUND OF THE INVENTION

The tear film, which is the interface between the external environmentand the ocular surface, has several different functions. It forms asmooth refractive surface over the otherwise irregular corneal surfaceand lubricates the eyelids. Moreover, it maintains an optimalextracellular environment for epithelial cells of the cornea andconjunctiva where the electrolyte composition, osmolarity, pH, oxygenand carbon dioxide concentrations, nutrient and growth factorconcentrations are regulated within narrow limits.

Tears dilute and wash away noxious stimuli. They also provide anantibacterial system for the ocular surface and serve as an entrypathway for polymorphonuclear leukocytes in the case of injury to theocular surface. As tears have many and varied functions, it is notsurprising that they have a complex structure and are produced byseveral different sources.

The tear film consists of three layers. The inner layer is a mucouslayer that coats the cornea and conjunctiva. It was previously thoughtto be 1 μm, but new evidence suggests that it may be far thicker. Themucous layer consists of mucins, electrolytes, water, IgA, enzymes,glycocalyx, microvilli, immunoglobins, and glycoproteins. The middlelayer is an aqueous layer that is about 7 μm thick. This layer containselectrolytes, water, IgA, and proteins, many of which are antibacterialenzymes. Finally. the outer layer is a lipid layer about 0.1 μm thick,which floats on the aqueous layer. The lipid layer contains a complexmixture of hydrocarbons, squalene, wax esters, cholesterol esters,triglycerides, diglycerides, monoglycerides, free fatty acids, freecholesterol, phospholipid, sterol esters, and polar lipids.

Each layer of the tear film is secreted by a different set of orbitalglands.

The lipid layer is secreted primarily by the meibomian glands located inthe tarsal plates of the lower and upper lids. The glands lie in a rowat the edge of the upper and lower eyelids and their ducts open directlyonto the inner margin of the eyelids. There are approximately 30 to 40meibomian glands in the upper lid and 20 to 30 smaller glands in thelower lid. Each gland has an orifice that opens on the lid marginbetween the tarsal “grey line” and the mucocutaneous junction. Thesebaceous glands of Zeis, located at the palpebral margin of the tarsus,and the aprocine glands of Moll, located at the roots of each eyelash,also secrete lipid that is incorporated into the tear film.

Sebum, also called meibum, the meibomian gland secretion, increases thesurface tension of the tear film and decreases its rate of evaporation.The evaporation rate of the normal tear film is low because of theprotective lipid layer. Approximately 10% to 20% (0.085 μL/minute) ofthe total tears secreted are lost by evaporation. In the absence of theprotective lipid layer, the rate of evaporation is increased 10 to 20times (1.7 μL/minute).

Meibomian gland secretions contribute to the formation of a stable tearfilm. Meibomian gland dysfunction may result in dry eye syndrome,keratoconjunctivitis and contact lens intolerance, presumably due to aninadequate or a compromised tear film which is secondary to themeibomian gland dysfunction itself. Meibomian gland dysfunction may beoften induced by soft contact lens wear, whilst mebomianitis may resultfrom hard contact lens wear.

There are two major types of dry eye syndromes. Aqueous deficient dryeye syndrome is caused primarily from a lack of tear secretion from thelacrimal gland, whereas evaporative dry eye syndrome is typically causedby lipid insufficiency, a condition related to meibomian glanddysfunction. Both syndromes often co-exist. It is thought that meibomiangland dysfunction may be caused in response to decreased androgenlevels. Human lacrimal glands, meibomian glands and other ocular tissueshave androgen receptors. The meibomian gland in particular appears to bea principal target site for androgen activity on the ocular substrate.Androgens appear to stimulate meibomian gland cells to produce lipidswhich maintains tear film stability and prevent tear film evaporation.Decreased androgen levels frequently occur with fluctuating hormonalchanges associated with menopause, pregnancy, lactation and through theuse of oral contraceptives. It is also associated with the ageingprocess in men and women. Auto immune diseases such as Sjörgen'ssyndrome, rheumatoid arthritis, diabetes, thyroid abnormality, asthma,cataracts, glaucoma and lupus appear to correlate with the presence ofmeibomian gland dysfunction and evaporative dry eye syndrome.

Certain medications such as antidepressants, decongestants, diuretics,ulcer medication, tranquillisers and beta blockers can also decrease thebody's ability to produce lubricating lipids.

Use of antiandrogen medications for prostatic hypertrophy or cancer alsoappear to correlate with the incidence of meibomian glad dysfunction andevaporative dry eye syndrome.

Evaporative dry eye syndrome may also be caused by environmentalconditions such as exposure to smoke, fluorescent lights, air pollution,wind, heaters, air conditioning and dry climates.

Similarly, behavioural patterns, particularly the tendency for VDU usersto ignore the normal blinking process, may also interrupt tearproduction.

Contact lens wearers appear to be particularly susceptible toevaporative dry eye syndrome. Contemporary contact lenses are of twoprimary types: rigid gas permeable lenses (hard) and hydrogel lenses(soft) comprising between 30% to over 85% water of hydration. Rigid gaspermeable lenses are commonly formed from a co-polymer ofmethylmethacrylate and silicon, termed siloxaneacrylate.

The tear film thickness on the eye is reported to be up to 10 microns,decreasing to 4.5 microns between blinks. The tear film is relativelythin when compared with the thickness of any contact lens, which variesfrom a minimum of 30 microns to an average of 60-120 microns, and over250 microns for lenses of considerable optical power. Thus, the sheermass of any contact lens may compromise the specific functions of thetear film which include the flushing action, the prevention ofdesiccation of the ocular tissue, the lubrication of the ocular andpalpebral surfaces, the formation of an optically smooth curved surface,a vehicle for oxygen and carbon dioxide transport. and the defence ofthe cornea against trauma, infection or disease. The role of the lipidlayer in preventing evaporation is relevant to contact lens wear. If themeibomian glands are obstructed, essentially eliminating the lipidlayer, the rate of evaporation dramatically increases by a factor of 10to 20.

The lipid layer on the surface of all contact lenses is compromised ascompared to the lipid layer of the cornea without the contact lenses. Awell-fitted contact lens has to rest on a continuous aqueous tear layersandwiched between the lens and the epithelium, and it has to be coatedwith a continuous tear film complete with a superficial lipid layer.However, all contemporary contact lenses are unable to mimic the ocularsurface properties, and therefore a comparable tear film on the lenssurfaces is unable to form.

A lipid layer does not form on hard lenses. There are conflictingreports regarding the presence and/or characteristics of the lipid layerforming on soft lenses. Some claim the complete absence of a lipidlayer, while others report it as present but thin, its depth beingdependent on the water content of the lens.

Clinical experience indicates that individuals without objective signsof dry eyes or subjective symptoms may experience classical dry eyesymptoms while wearing contact lenses. When the contact lens is placedon the eye, the lens alters the normal structure of the tear film andaffects its rate of evaporation. It is thought that the lipid layer iscompromised causing dehydration of the aqueous layer to accelerate andtears to macerate the skin.

The present invention seeks to overcome at least some of theaforementioned disadvantages

SUMMARY OF THE INVENTION

In accordance with one aspect of the invention there is provided anophthalmic fluid, wherein the ophthalmic fluid is arranged in use toprovide a protective film across a tear film of an ocular substrate, theophthalmic fluid comprising at least one glyceride of formula (I):

wherein R¹=R²=R³ is —O—CO—R; or R¹=R³ is O—CO—R when R² is OH, or R¹ is—O—CO—R when R²=R³=OH; R is a fatty acid residue containing at least oneunsaturated bond, and R is the same or different when R¹=R³ or R¹=R²=R³.

DESCRIPTION OF THE INVENTION

The ophthalmic fluid of the present invention contains at least onetriglyceride, diglyceride, or monoglyceride of a fatty acid containingat least one unsaturated bond which is chemically similar to thosecompounds found naturally in the lipid layer of the tear film of theeye. Alternatively, the ophthalmic fluid of the present inventioncontains at least one triglyceride, diglyceride, or monoglyceride of afatty acid containing at least one unsaturated bond which is compatiblewith those compounds found naturally in the lipid layer of the tear filmof the eye. Preferably, the ophthalmic fluid of the present inventioncontains a compound which biomimics at least one component of the lipidlayer of the tear film of the eye. It will also be understood that theophthalmic fluid may contain mixtures of the abovementioned components.Furthermore, it will also be understood that the fatty acid residuescomprised in the diglyceride or triglyceride may be the same ordifferent.

Preferably, the ophthalmic fluid contains at least one triglyceride,diglyceride, or monoglyceride derived from a fatty acid containing atleast one unsaturated bond in a cis-configuration in the fatty acidresidue. However, glycerides derived from a fatty acid containing atleast one unsaturated bond in a trans-configuration in the fatty acidresidue may also be suitable. It is envisaged that the carbon chainlength of the fatty acid residue will range from 16 carbon to 20 carbonatoms. However, the carbon chain length may vary from that provided thatthe melting point of the triglyceride, diglyceride or monoglyceride issufficiently low for handling and application purposes. Preferrably, theophthalmic fluid contains at least one triglyceride, diglyceride ormonoglyceride derived from oleic acid, linoleic acid, linolenic acid,palmitoleic acid, arachidonic acid, or mixtures thereof.

While it is possible for the fatty acid of the glyceride of formula (I)to be administered alone, it is also possible to topically apply theglyceride of the present invention to the ocular substrate as apharmaceutical composition. The pharmaceutical composition of thepresent invention comprises at least one glyceride, as defined above, inadmixture with one or more suitable carriers or diluents therefor andoptionally other therapeutic ingredients. The carrier(s) and diluent(s)must be “suitable” in the sense of being compatible with the othercomponents of the formulation and not deleterious to the recipientthereof.

Naturally occurring vegetable oils, such as grapeseed oil, havingglycerides derived from linoleic acid may also be used as an ophthalmicfluid in accordance with the present invention, particularly if thephysical properties of such an oil is to form oily droplets which willcoat the inner surface of the contact lens, and the chemical propertiesof the components of said oil are such as to be superficially recognisedby the ocular substrate as components of the lipid layer of the tearfilm of the eye.

Glycerides characteristically form oily droplets. Upon application ofthe ophthalmic fluid of the present invention to an inner surface of thecontact lens, the glyceride molecules bond together to form a glyceridefilm which coats the inner surface of the contact lens.

The glyceride film has two purposes, one of which is to mask the foreignnature of the contact lens from the ocular substrate. The glyceride filmis comprised of glycerides which are chemically similar to thosecompounds found naturally in the lipid layer of the tear film of theeye. In this way, the coated contact lens is superficially recognised bythe ocular substrate as a substance that is naturally produced by theeye. Irritation arising from rejection of an alien substance in the eyeis subsequently reduced.

The purpose of the lipid layer of the tear film is to provide aneffective barrier against tear loss by dehydration and maceration. Whenthe lipid layer is compromised upon application of the contact lens tothe ocular substrate, the rate of evaporation from the tear filmincreases. The contact lens wearer consequently experiences discomfortand dry eye syndrome symptoms. The second purpose of the glyceride filmon the inner surface of the contact lens is thus to reinforce the lipidlayer of the tear film. The compromised lipid layer is effectivelyrebuilt or reinforced by the application of a glyceride film comprisedof substances which are naturally produced and secreted by the eye toform the lipid layer in the tear film.

The resulting reduction in tear loss and minimisation of lipid layerdisintegration is noticed by the eye as a reduction of the irritationusually associated with the application of contact lenses. Hence, thecontact lens wearer experiences increased wear comfort.

The ophthalmic fluid of the present invention is suitable for use withgas permeable (hard) contact lenses or hydrogel (soft) contact lenses.In use, 2-3 drops of the ophthalmic fluid of the present invention areplaced onto the inside surface of the contact lens. The ophthalmic fluidis then distributed to cover fully and evenly the inside surface of thecontact lens by rubbing the ophthalmic fluid into the lens with afingertip or any other suitable applicator. It is envisaged that theophthalmic fluid will be biologically sterile.

The lipid layer of the tear film is also compromised in subjects whoexperience dry eye syndrome and meibomian gland dysfunction. Theophthalmic fluid of the present invention acts to reinforce the lipidlayer of the tear film because its components are either chemicallysimilar to, chemically and/or biologically compatible with, or biomimicat least one component naturally occurring in the lipid layer of thetear film. Thus the ophthalmic fluid of the present invention issuitable for the preparation of medicaments for the prevention andtreatment of dry eye syndrome. The ophthalmic fluid of the presentinvention is suitable for the preparation of medicaments for thetreatment of meibomian gland dysfuntion.

The present invention is further illustrated by the following examples.

The inside of a contact lens was coated with 2-3 drops of the ophthalmicfluid of the present invention and fitted to the subject in theconventional manner. The subject reported on the perceived ease ofinserting the coated lens, the subject's sensual reaction to the coatedlens and the resulting vision through the coated lens, in relation tohard and soft contact lenses.

EXAMPLE 1

Triolein(1,2,3-tri(cis-9-octadecenoyl)glycerol) (Sigma Chemicals, 99%).

The subject reported that a gas permeable (hard) lens coated withtriolein was very comfortable to insert, the edges of the lens seeminglysmoothed out so as to reduce, but not totally eliminate, the normaldiscomfort associated when inserting a hard lens. Once inserted, thesubject could not feel the presence of the coated lens. The subject'svision through the coated lens was excessively and persistently blurred.Excess triglyceride did not drain into the lacrimal ducts, and had to bephysically removed.

The subject reported that a hydrogel (soft) lens coated with trioleinwas very difficult to insert, and did not noticeably ameliorate thenormal discomfort associated when inserting a soft lens. The subject'svision through the coated lens was clear.

EXAMPLE 2

Trilinolein(1,2,3-tri(cis,cis-9,12-octadecadienoyl)glycerol) (SigmaChemicals, 99%).

The subject reported that a gas permeable (hard) lens coated withtrilinolein was very comfortable to insert. In comparison to a hard lenscoated with triolein, however, the sensation caused by the edges of thelens on the eye was not reduced to the same extent by a hard lens coatedin trilinolein. Once inserted, the subject could not feel the presenceof the coated lens. The subject initially experienced blurred visionwhich cleared after approximately 60 seconds. Excess triglyceridedrained into the lacrimal ducts, and a residue did not remain on the eyesurface or eyelid. The subject reported no tear expulsion.

The subject reported that a hydrogel (soft) lens coated with trilinoleinwas easy to insert, and produced a noticeable amelioration of the normaldiscomfort associated when inserting a soft lens. Once inserted, thesubject could not feel the presence of the coated lens. The subject'svision through the coated lens was immediately clear. Excesstriglyceride drained into the lacrimal ducts, and a residue did notremain on the eye surface or eyelid. The subject reported no tearexpulsion.

EXAMPLE 3

Tripalmitolein(1,2,3-tri(cis-9-hexadecenoyl)glycerol) (Sigma Chemicals,98%).

The subject reported that a gas permeable (hard) lens coated withtripalmitolein was very comfortable to insert. In comparison to a hardlens coated with triolein, however, the sensation caused by the edges ofthe lens on the eye was not reduced to the same extent by a hard lenscoated in tripalmitolein. Once inserted, the subject could not feel thepresence of the coated lens. The subject's vision through the coatedlens was excessively blurred. Excess tripalmitolein did not drain intothe lacrimal ducts, and had to be physically removed.

The subject reported that a hydrogel (soft) lens coated withtripalmitolein was very difficult to insert as the lens was moreadhesive to a finger coated with the fluid than to the actual ocularsubstrate. However, once the lens was inserted onto the eye, the subjectfound the soft lens coated with tripalmitolein to be comfortable. Thesubject's vision through the coated lens was blurred.

EXAMPLE 4

Trilinolenin(1,2,3-tri(cis,cis,cis-9,12,15-octadecatrienoyl)glycerol)(Sigma Chemicals, 98%).

The subject reported that although a gas permeable (hard) lens coatedwith trilinolenin was easy to insert, the subject experienced extremeirritation with increased tear production and maceration of the ocularsubstrate. The subject's vision through the coated lens was blurred.

The subject reported that a hydrogel (soft) lens coated withtrilinolenin was difficult to insert, the lens becoming quite greasy tohandle. However, once the soft lens coated with trilinolenin wasinserted onto the ocular substrate, the coated lens was comfortable towear. The subject initially experienced blurred vision which clearedafter 2 minutes.

EXAMPLE 5

Triarachidonin(1,2,3-tri(cis,cis,cis,cis,-5,8,11,14-eicosatetraenoyl)glycerol)(Sigma Chemicals, 98%).

The subject reported that a gas permeable (hard) lens coated withtriarachidonin was easy to insert with no residual greasy feel. Onceinserted, the coated lens was comfortable to wear. The subject did notexperience tear production or maceration. The subject's vision throughthe coated lens was excessively and persistently blurred. The subjectreported that a hydrogel (soft) lens coated with triarachidonin was easyto insert with no residual greasy feel. However, a soft lens coated withtriarachidonin did not produce any noticeable improvement in thewearer's comfort. The subject experienced increased tear production uponinsertion of the soft lens, but no maceration. The subject had clearvision.

The subject noticed that the soft lens became cloudy or frosty inappearance upon application of triarachidonin onto its surface.

EXAMPLE 6

Safflower Oil (Melrose, Organic Unrefined, Cold Pressed). Composition:(per 100 g) Saturates Palmitic  7 g Stearic  2 g Monounsaturates Oleic12 g Polyunsaturates Linoleic 78 g

The subject reported that a gas permeable (hard) lens coated withsafflower oil was difficult to insert with a distinct residual greasyfeel. The subject experienced a painful stinging sensation uponinsertion of the coated lens onto the ocular substrate combined withmaceration. The subject's vision through the coated lens was excessivelyand persistently blurred.

The subject reported that a hydrogel (soft) lens coated with saffloweroil was difficult to insert, the lens becoming quite greasy to handle.The subject experienced a painful stinging sensation upon insertion ofthe coated lens onto the ocular substrate. The subject's vision throughthe coated lens was blurred. The excess oil did not drain into thelacrimal ducts, and had to be physically removed

EXAMPLE 7

Walnut Oil (Anglia Oils Ltd). Composition: Saturates Palmitic  8-11%Monounsaturates Oleic 15-18% Polyunsaturates Linoleic 51-62% Linolenic10-19%

The subject reported that a gas permeable (hard) lens coated with walnutoil was difficult to insert with a distinct residual greasy feel. Thecoated lens was comfortable to wear, the only discomfort arising fromthe edges of the lens. The subject's vision through the coated lens waspersistently blurred.

The subject reported that a hydrogel (soft) lens coated with walnut oilwas difficult to insert, the lens becoming quite greasy to handle. Thesubject experienced a painful persistent irritation upon insertion ofthe coated lens onto the ocular substrate. The coated lens also producedexcessive tear production. The subject's vision through the coated lenswas blurred. The excess oil did not drain into the lacrimal ducts, andhad to be physically removed

EXAMPLE 8

Canola Oil (Melrose, Organic Unrefined). Composition: (per 100 g)Saturates Palmitic 7.0 g Stearic 7.0 g Monounsaturates Undetermined 64.0g  Polyunsaturates Linoleic 19.5 g  Linolenic 9.5 g

The subject reported that a gas permeable (hard) lens coated with canolaoil was difficult to insert with a distinct residual greasy feel. Thesubject experienced extreme discomfort and irritation upon insertion ofthe coated lens onto the ocular substrate combined with maceration andexcessive tear production. The subject's vision through the coated lenswas excessively and persistently blurred.

The subject reported that a hydrogel (soft) lens coated with canola oilwas difficult to insert, the lens becoming quite greasy to handle. Thesubject experienced a painful stinging sensation upon insertion of thecoated lens onto the ocular substrate, combined with maceration andexcessive tear production. The subject's vision through the coated lenswas blurred.

EXAMPLE 9

Grapeseed Oil (Aurora). Composition: Saturates Undetermined 7-8%Monounsaturates trace Polyunsaturates Linoleic 72-75% Linolenic trace

The subject reported that a gas permeable (hard) lens coated withgrapeseed oil was easy to insert and comfortable to wear. The subjectnoticed slight discomfort associated with the edges of the lens on theeye which was not reduced to the same extent as with a hard lens coatedwith triolein. The subject initially experienced blurred vision whichcleared after approximately 30 seconds. An oily residue did not remainon the eye surface or eyelid. The subject reported no tear expulsion.

The subject reported that a hydrogel (soft) lens coated with grapeseedoil was easy to insert, and produced a noticeable amelioration of thenormal discomfort associated when inserting a soft lens. Once inserted,the subject could not feel the presence of the coated lens. Thesubject's vision through the coated lens was initially blurred, butcleared after 30 seconds.

Excess grapeseed oil drained into the lacrimal ducts, and a residue didnot remain on the eye surface or eyelid. The subject reported no tearexpulsion or maceration.

In light of the results of Examples 1 to 9, it is envisaged than theophthalmic fluid of the present invention may contain a glyceridederived from oleic acid in combination with a glyceride derived fromlinoleic acid. The glyceride derived from oleic acid imparts a characterto the ophthalmic fluid in which the edges of a hard lens are seeminglysmoothed out so as to reduce the normal discomfort associated wheninserting a hard lens, whilst the glyceride derived from linoleic acidprovides improved wear comfort and clear vision through the lens.

Modifications and variations as would be apparent to a skilled addresseeare deemed to be within the scope of the present invention.

1. A method of providing a protective film intermediate a lipid layer ofa tear film of an ocular substrate and a contact lens, comprisingtopically applying an ophthalmic fluid to the contact lens beforeapplying the contact lens to the ocular substrate, wherein theophthalmic fluid comprises at least one glyceride of formula (I):

wherein R¹=R²=R³ is O—CO—R; or R¹=R³ is O—CO—R when R² is OH; or R¹ isO—CO—R when R²=R³=OH; R is a fatty acid residue comprising 16-20 carbonatoms and containing at least one unsaturated bond, and R is the same ordifferent when R¹=R³ or R¹=R²=R³.
 2. The method according to claim 1,characterized in that irritation to the ocular substrate associated withthe application of the contact lens to the ocular substrate is reduced.3. The method according to claim 1, characterized in that the methodprevents and treats dry eye syndrome experienced by contact lenswearers.
 4. The method according to claim 1, characterized in that themethod reinforces the lipid layer of the tear film of the ocularsubstrate upon application of the contact lens to the ocular substrate.5. The method according to claim 1, characterized in that the fatty acidresidue contains at least one unsaturated bond in a cis-configuration.6. The method according to claim 1, characterized in that the ophthalmicfluid contains at least one triglyceride, diglyceride, or monoglyceridederived from oleic acid, linoleic acid, linolenic acid, palmitoleicacid, arachidonic acid, or mixtures thereof.
 7. A method of providing aprotective film intermediate a lipid layer of a tear film of an ocularsubstrate and a contact lens, comprising topically applying anophthalmic fluid to the contact lens before applying the contact lens tothe ocular substrate, wherein the ophthalmic fluid consists essentiallyof at least one glyceride of formula (I):

wherein R¹=R²=R³ is O—CO—R; or R¹=R³ is O—CO—R when R² is OH; or R¹ isO—CO—R when R²=R³=OH; R¹ is a fatty acid residue comprising 16-20 carbonatoms and containing at least one unsaturated bond, and R is the same ordifferent when R¹=R³ or R¹=R²=R³.
 8. The method according to claim 7,characterized in that irritation to the ocular substrate associated withthe application of the contact lens to the ocular substrate is reduced.9. The method according to claim 7, characterized in that the methodreinforces the lipid layer of the tear film of the ocular substrate uponapplication of the contact lens to the ocular substrate.
 10. The methodaccording to claim 7, characterized in that the fatty acid residuecontains at least one unsaturated bond in a cis-configuration.
 11. Themethod according to claim 7, characterized in that the ophthalmic fluidcontains at least one triglyceride, diglyceride, or monoglyceridederived from oleic acid, linoleic acid, linolenic acid, palmitoleicacid, arachidonic acid, or mixtures thereof.